Photochemical preparation of 17, 20-hydroxy-ketones of the pregnane series



Patented Dec. 15, 1953 PHOTOCHEMICAL PREPARATION OF 17,20-

HYDROXY-KETONES OF THE PREGNANE SERIES Karl Miescher, Riehen, and JuliusSchmidlin,

Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Inc.,Summit, N. J.

No Drawing. Application September 21, 1951,

Serial No. 247,766

Claims priority, application Switzerland October 12, 1950 Claims. (Cl.204158) This invention relates to the preparation of saturated orunsaturated 17,20-hydroxy-ketones of the pregnane series having a free,esterified or etherified hydroxyl group in 2l-position.

Such hydroxy-lzetones of the pregnane series are of very greatimportance. Thus, for example, cortisone A-3,l1,20-triketo-l'7a,2l-dihydroxypregnene-and substance s-M 3,20diketo- 17a,2l-dihydroxy-pregnene-are 17,20-hydroxyketones. Variousprocesses for the preparation of these compounds are known. Thus, theymay be produced by treatment of the corresponding A -2l-acetoxy-pregnenecompounds with hyroxylating agents, such as osmium tetroxide, andsubsequent partial oxidation of the thus-obtained 17,20,21-triols. Thisprocess requires at least three stages for the production of the desired17,20-hydroxy-ketones. The yields are very unsatisfactory, especially inthe last stage.

A primary object of the present invention is the embodiment of a processwhich is free of the deficiency of the known processes, and wherein,more particularly, the number of stages is materially reduced and theresultant yield materially increased.

This object is realized by the process of the present invention,according to which, briefly stated, a 17,20-hydroXy-ketone is obtaineddirect- :ly by reacting a pregnene compound with thegrouping =CH-CHzX inl'l-position, in which X,

indicates a free, esterified or etherified hydroxyl group with a metaloxide which is capable of adding onto carbon-carbon double bonds andwith a peroxide compound, the reactants being exposed to light duringthe reaction, and the formed 17,2G-hydroxy-ketone being thereafterisolated from the reaction mixture. The process according to the presentinvention gives essentially better yields than the known processes and,moreover, comprises only one reaction stage.

As starting materials for the process according to this invention, thereare used, more particu-i. iarly, esterified or etherified21-hydroxy-preg-.

nene compounds, for example such as contain in zl-position an acyloxygroup, for example the acetoxy, prcpionyloxy, succinyloxy, benzoyloxy ortosyloxy group, or a halogen atom or an alkoxy group, for example themethoxy or ethoxy group,

or a hydroxyl group etherified with a sugar residue, such as d-glucose,galactose, maltose or lactose. The starting materials can in addition bealso substituted in 5-, 6-, 7-, 12- and especially in 3- andll-position, for example by free or functionally converted keto orhydroxyl groups, as by acyloxy groups, for example the acetoxy,propionyloxy, benzoyloxy or tosyloxy group, or halogen atoms, by alkoxygroups, such as the methoxy or ethoxy group, or by epoxy groups forexample in 3,9-position. They may further also contain double bonds in3-, 4-, 5-, 9- and/or ll-position. If necessary such double bonds aretemporarily protected in the manner known per se, for example bysaturation with halogen or hydrogen halide or by conversion intopentacyclic isosteroids.

The aforementioned metal oxides are especially those of the highestvalency stages of heavy metals of the groups 5 to 8 of the periodicsystem; for example, osmium tetroxide, further also tungsten trioxide.The preferred peroxide compound is hydrogen peroxide. Other organicperoxide compounds are also suitable such for example as alkyl peroxidesor peracids, for example, performic, peracetic, perpropionic,perbutyric, perbenaoic and monoperphthalic acid. The reaction isadvantageouslycarried out in an anhydrous or aqueous diluent. Especiallysuitable are tertiary carbinols, for exampletertiary butanol, and alsoethers, lower fatty acid esters and chlorinated hydrocarbons, such asmethylene chloride or carbon tetrachloride. For the irradiation bylight, various light sources can be used with or without an ultra-violetconstituent, as for example the light of electric incandescent lamps,quartz lamps, are lamps or also strong natural light such as directsunlight.

In copending application Ser. No. 209,516, filed February 5, 1951, thereis described a process for the preparation of a 17,20-hydroxyketonewhich comprises reacting a pregnene having the grouping =CHCH2X in 17-position, X representing a member selected from the group consisting offree, esterified or etherified hydroxyl, with osmium tetroxide and witha member selected from the group consisting of hydrogen peroxide, analkyl peroxide, and a peracid, and isolating the resultant hydroxyketonefrom the reaction mixture. The irradiation by light according to thepresent invention offers principally the advantage of increasingconsiderably the velocity of reaction. In addition, secondary reactionsare excluded to a far-reaching extent.

The products of manufacture may be used as medicaments or asintermediates. Some of them are new. Thus, A-3,20-diketo-l'Ia-hydroXy-Zlhalogen-pregnenes, for example A-3,1l,20-triketo-17a-hydroxy-2l-bromo-pre nene or A -3,2O-diketo-1'7a-hydroxy-21-bromo-pregnene, are new compounds which are ofgreat importance as intermediates in the manufacture of therapeuticallyactive substances.

The following examples illustrate the invention, parts and percentagesbeing by weight unless otherwise indicated, and the relation betweenparts by weight and parts by volume being the same as that between thekilogram and the liter:

Example 1 3.565 parts by weight of A -3keto21* acetoxy-pregnadiene aredissolved in 50 parts by volume of tertiary butanol and treated with13.5 parts by volume of a 1.5-molar solution of hydrogen peroxide intertiary butanol. While exposing the resultant mixture to light from anelectric lamp and continuously stirring, there are added, within 5minutes, parts by volume of a solution of 0.255 part by weight of osmiumtetroxide in parts by volume: of tertiary butanol, the remainder beingadded in portions of one part by volume each at intervals of 2 hours.After exposure to light for a further 16 hours with stirring, a solutionof 1.5 parts by weight of 85 per cent. sodium sulphite in 200 parts byvolume of 50 per cent. aqueous methanol isadded and the mixture isshaken for' 24 hours at room temperature. The organic solvents are thendistilled off with the simultaneous addition of 100 parts by volume ofwater and the reaction product is taken up in methylene chloride, thecombined methylene chloride solutions washed several times with water,dried with sodium sulphate and evaporated.

The residue is dissolved in 12.5 parts by volume of anhydrous pyridine,7.5 parts by volume of acetic anhydride added and the mixture, fromwhich after only a few minutes crystals begin to separate, allowed tostand for 16 hours at 20 C. The easily volatile substances are thendistilled off under reduced pressure, with the aid of a water pump, at40-50 C. bath temperature and the residue stirred with 5 parts by volumeof ether. After standing for several hOllls, the brown-colored motherliquor is filtered with suction and the crystals washed with a littleether. By recrystallizing once from acetone, the A 3,20 diketo 17ahydroxy- 2-1-- acetoxy-pregnene of the formula CHzOCOCHs; CH5 CH;

Ewample 2 3.565 parts by weight of A -3-keto-21- acetoxy-pregnadiene aredissolved in 150 parts by volume of anhydrous ether and treated with21.6 parts by volume of a 1.85-molar ethereal hydrogen peroxidesolution, which corresponds to a doubled molecular proportion ofhydrogen peroxide compared with Example 1. With exposure to light froman electric lamp and continuous stirring, there are added, within 5minutes, a first quantity of 5 parts by volume of a solution of 0.255part by weight of osmium tetroxide in 25 parts by volume of anhydrousether, the remainder being added in portions of 1 part by volume each atintervals of 2 hours. When the addition is complete the whole is stirredfor a further 24 hours with exposure to light.

The working up takes place in a corresponding manner to that describedin Example 1. From the first crystal fraction there is isolated, by asingle recrystallization from acetone, pure A 320 diketo-17ahydroxy 21acetoxy pregnene which has a melting point of 236-238 C. and specificrotation [a] =+i4 (c=0.531 in acetone).

Example 3 3.775 parts by weight of finely powdered A 3 keto 21 bromopregnadiene are covered with 50 parts by volume of tertiary butanol,treated with 13.5 parts by volume of a 1.5-molar solution of hydrogenperoxide in tertiary butanol and subjected to the addition, whileexposing to light from an electric lamp and continuously stirring,within 32 hours of a solution of 0.255 part by weight of osmiumtetroxide in 25 parts by volume of tertiary butanol. When the additionis complete the mixture is stirred for a further 48 hours with exposureto light. The tertiary butanol is then distilled off under reducedpressure, while allowing 100 parts by volume of water to flow in, andthe reaction product is taken up in methylene chloride. The methylenechloride solution is washed with water, dried with sodium sulphate andevaporated. From a very concentrated solution of the residue in ether,on standing, the A"*-3,20- diketo-17a-hydroxy-21-bromo-pregnene of theformula 0112B: CH: CH: g

crystallizes out in fine granular form. By recrystallization fromacetone with decolorization with active carbon, the pure bromoketol isobtained in the form of colorless grains which melt at 187-189" C. withdecomposition.

In an analogous manner M -3-keto-2lchloropregnadiene may be oxidized toform M- 3,2() diketo 17a hydroxy 21 chloro pregnene. Analogous compoundsmay also be used, which carry in 11 or 12-position a substituent, suchas a keto group. In this manner, A 3,11;2O-triketo-17a-hydroxy-21-bromo-pregnene may be obtained.

1.05 parts by weight of A -3,2O-diketo-17a-hydroxy-2l-bromo-pregnene and9.82 parts by weight of finely powdered anhydrous potassium acetate arecovered with parts by volume of dry acetone and the mixture boiled forone hour. The solvent is thereupon evaporated in vacuum and the residue,after the addition of water, extracted with ether. The ether extractsare washed with 2 per cent. sodium bicarbonate solution and water, driedwith sodium sulphate andthe ether distilled off. From the crude productthere isobtained. by recrystallization from acetone the A 3,20diketo-17a-hydroxy-21- ecetoxy-pregnene melting at 236-238" C. Describedin Examples 1 and 2.

Example 4 7.15 parts by weight of A "-3-keto2l-acetoxypregnadiene aredissolved in 300 parts by volume of ether, treated with 29.5 parts byvolume of a 1.7-molar ethereal solution of hydrogen peroxide and asolution of 0.51 part by weight of osmium tetroxide in 100 parts byvolume of ether slowly introduced drop by drop with stirring, whileexposing to strong light.

After a reaction period of 20 hours the Whole is diluted with ether, thesolution extracted by shaking several times with water for removal ofexcess of hydrogen peroxide, dried with sodium sulphate, filtered andevaporated.

The residue is dissolved in 250 parts by volume of methanol, treatedwith a solution of 3 parts by Weight of sodium sulphite in 50 parts byvolume of water and the whole boiled for onehour under reflux. Thereaction product is extracted from the cooled mixture with much etherand the ether solution washed several times with water and dried withsodium sulphate, filtered and the solvent distilled off.

For reacetylation of the crude product which has become partiallysaponified in Zl-p-osition, the residue is dissolved in 50 parts byvolume of anhydrous pyridine and mixed with 30 parts by volume of aceticanhydride. After 16 hours standing at 2 -D-25 C. the liquid iscompletely evaporated in vacuum at a bath temperature of 35-40" C. Fromthe reaction product by re-- crystallisation with ether crude A-3,20--dil:etoi'ia-hydroxy 21 acetoxy-pregnene is obtained, which aftera single recrystallization from acetone-ether melts at 236-238 C.

From the mother liquor there is obtained by adsorption on aluminiumoxide a further quantity of pure A-3,2G-diketo-17a-hydroxy-21-acetoxypregnene.

EmampZe 5 3.725 parts by weight of A -3,11-diketo-21 acetoxy-pregneneare dissolved in 150 parts by volume of 0.2-molar hydrogen peroxide intertiary butanol. To the solution is added within 32 hours with stirringand exposing to the light of electric lamps a solution of 0.255 part byweight or" osmium tetroxide in 25 parts by volume of tertiary butanol.From the time when the addition is complete stirring is continued for afurther 24 hours at 2530 C. The reaction mixture diluted with 159 partsby volume of methylene chloride is thereupon shaken for 24 hours with asolution of 3 parts by weight of 85 percent. sodium sulphite in 75 partsby volume of water, afterwards diluted With water and then extractedseveral times with methylene chloride. The methylene chloride solutionsare thoroughly washed with water, dried with sodium sulphate andevaporated.

For re-acety1ation of the reaction product which has become partlyhydrolyzed in 2l-position, the residue is dissolved in 12.5 parts byvolume of anhydrous pyridine and mixed with 7.5 parts by volume ofacetic anhydride. After 16 hours standing at room temperature thereaction mixture is evaporated in vacuum, the residue taken in methylenechloride and the soluticn washed consecutively with N -hydrochloricacid, O.5N-sodiumbicarbonate solution and wa-= in colourless crystals ofM. P. 232-2342 0. (with discoloration) and of specific rotation ial z=+89i l (0:0.518 in acetone) The specified process may also be carriedout with a A -3-keto-pregnadiene carrying an etherified hydroxy group in21-position Thus, as a result of the oxidation of A 3-keto-2lmethoxypregnadiene and A 3 seto-21- benzyloxy pregnadiene, A-3,20-diketo-17a-hydroxy-21-n1ethoxy-pregnene and A3,2G-diketolia-hydroxy 21 benzyloxy-pregnene are obtained.

Example 6 3.145 parts by weight of A -3-keto-21-hydroxy-pregnadiene aredissolved in 50 parts by volume of tertiary butanol and treated with12.1 parts of volume of a 1.66-molar solution of hydrogen peroxide intertiary butanol. While exposing the resultant mixture to' the light ofquartz lamps and with continuous stirring there are added Within 3minutes 10 parts by volume of a solution of 0.255 part by Weight ofosmium tetroxide in 25 parts by volume of tertiary butanol, theremainder being added in the course of 30 hours. For completion of thereaction the mixture is subsequently stirred and exposed to light for afurther 14 hours. Dilution is then effected with 250 parts by volume ofmethanol followed by treatment with a solution of 3 parts by weight ofper cent. sodium sulphite in 65 parts by volume of water and boiling for30 minutes under reflux. After cooling to 30-40 C. the organic solventsare distilled off in vacuum While 250 parts by volume of Water areallowed to flow in and the reaction product is taken up in methylenechloride. The methylene chloride solution is washed several times withwater, dried with sodium sulphate and evaporated.

The A -3,20-diketo-17a,2l-dioxy-pregnene obtained is acetylated asdescribed in Example 1 and further worked up. By recrystallization firstfrom a little acetone and then from acetoneether pure A-3,20-diketol'ia-hydroxy-zi-acetoxy-pregnene is obtained of M. P.236-238 C. and specific rotation [a] :+123i4 (0:0.522 in acetone).

- Example 7 0.128 part by weight of osmium tetroxide is added to asolution of 1.783 parts by weight of A -3-keto-2l-acetoxy-pregnadiene in60 parts by volume of ether. While stirring, and exposing to a stronglight, 46 parts by volume of a 0.217- mo1ar solution,ofmono-perphthalicacid in ether are allowed to flow in in the course of 6 hours. When theaddition is complete, stirring and exposing to light is continued for 16hours, then the reaction mixture is diluted with 100 parts by volume ofmethanol and shaken for 12 hours with a solution of 1.5 parts by weightof sodium sulphite of 85 per cent. strength in 100 parts by volume ofwater. The organic solvents are removed in vacuo, the oxidation productis taken up in 500 parts by volume of ether and the ether solutions arewashed consecutively with an acidified 0.5-molar solution of potassiumiodide, water, a 0.5-molar solution of sodium-thiosulphate, a 0.5-colarsodium-carbonate solution and water. The combined other solutions aredried with sodium sulphate, filtered and evaporated. The residue isdissolved in 7.5 parts by volume of anhydrous pyridine and mixed with4.5 parts by volume of acetic anhydride. After 14 hours standing withthe exclusion of moisture, the whole is evaporated at 45 C. under awater-jet vacuum and the acetylation product which is in partcrystalline is stirred with ether. After filtering with suction andrecrystallization from acetone the A-3,20-diketo-l'la-hydroxy-2l-acetoxy pregnene is obtained in colourlessprisms of M. P. 236-238 C.

Instead of monoperphthalic acid, perbenzoic acid may also be used inthis example.

Example 8 A solution of 7.13 parts by weight of M -3-keto-2l-acetoxy-pregnadiene in 50 parts by volume of tertiary butanol istreated with 20.5 parts by volume of a 1.95-molar solution oi tertiarybutyl hydroperoxide in tertiary butanol. While stirring and exposing tothe light of electric lamps, a solution of 0.231 part by weight ofosmium tetroxide in 25 parts by volume oi tertiary butanol is addedwithin 10 hours. Stirring and acetoxy-pregnene in colourless prisms ofM. P. I,

Example 9 A solution of 2.015 parts by weight of; 4 1313, e e e nene nN? part by olum of tertiary butanol is mixed with 1 0.2 parts by volumeof a 1.47-.molar solution of hydrogen per-. oxide in tertiary butanol.While exposing to the light of Strong and ent lamp a d. stirring asolution of 0.128 part by weight of osmium tetroxide in 25 parts byvolume of tertiary butanol is added within 5 hours. Stirring andexposing to light is continued for another 2 hours to complete h e n. Te T QUiQB. mi tur 5. 5 1.6 1 diluted with 100 parts by volume oimethanol and shaken for 16 hours with a solution of 1.5 parts by weightof sodium sulphite of 85 per cent. strength in 100 parts by volume ofwater. The organic solvents are thereupon completely distilled of? whileallowing '75 parts by volume of water to flow in and the oxidationproduct is taken up in ether. The other solutions are consecutivelywashed with water, 2% of sodium hydrogen carbonate solution and water,dried and evaporated.

The residue is dissolved in 12.5 parts by volume of anhydrous pyridineand mixed with 7.5 parts by volume of acetic anhydride. The solution isallowed to stand for 16 hours with the exclusion of moisture. The crudeacetylation product isolated by conventional means is chromatographed ina benzene solution over 50 parts by weight of aluminium oxide. After theremoval of easily separable portions with benzene, there is ob tained byelutriation with ether and subsequent recrystallization from a mixtureof benzene and methanol the 36,21 diacetoxy 17a. hydroxy-20-keto-allopregnane (diacetate of Reichsteins substance P) of theformula i mocooQL in colourless needles of M. P. 206208 C. and ofspecific rotation [al =-I-46:4(c=0.928 in cholorform) In an analogousmanner, there are obtained by starting from other A-33,21-diacyloxy-allopregnenes the corresponding 35,21-diacyloxy-17a-hydroxy-20-keto-allopregnanes, such as, for example,36,2l-dipropionyloxy-l7a-hydroxy-20- keto-allopregnane from A-iifizl-dipropionylhydroxy allopregnene. Alternatively, A" 21-acyloxy-pregnenes carrying a free hydroxy group in 3-position may alsobe employed in the process.

Example parts by volume of a 0.135-molar solution of hydrogen peroxidein tertiary butanol are poured on 0.372 part by weight of A-3-keto-1lfl-hydroxy-2l-acetoxy-pregnadiene. Upon occasional agitationand exposing to the light of strong neon lamps within 6 hours, asolution of 0.026 part by weight of osmium tetroxide in 4 parts byvolume of tertiary butanol is added. After a further 32 hours standing,and exposing to light the reaction mixture is diluted with parts byvolume of methanol, mixed with a solution of 0.3 part by weight ofsodium sulphite of 85 per cent. strength in 20 parts by volume of waterand shaken for 16 hours. The organic solvents are then distilled ofi invacuo at 0., the oxidation product is taken up in methylene chloride,the methylene chloride solutions are consecutively washed with water, 2%sodium hydrogen carbonate solution and water, dried with sodium sulphateand evaporated.

The residue is dissolved in 10 parts by volume of anhydrous methylenechloride, treated with 2.5 parts by volume of dry pyridine, the solutioncooled in ice water and mixed with 1.5 parts by volume of aceticanhydride. After 16 hours standing at 0 0., it is shaken with ice anddilute hydrochloric acid, diluted with a further quantity omoooom ofmethylene chloride, thoroughly washed with water and then with 2% sodiumhydrogen carbonate solution and water, dried and evaporated. The crudeacetylation product is dissolved in benzene and chromatographed over 10parts by weight of Florida bleaching earth.

As eluating agents, mixtures of benzene and ether, ether and chloroform,and chloroform and methanol are used. The fractions, melting between205. and 218 C. and capable of considerably reducing silver diamminesolution. are united and again purified by adsorption to Floridableaching earth. The oxidation product which is thus freed from slightlyreducing accompanying substances is recrystallized from a mixture ofethyl acetate and ether and from acetone whereby the A-3,2O-diketo-11B,17a-dihydroxy-21-acetoxy-pregnene (acetate ofReichsteins substance M) of the formula CHzOCOCH:

is obtained in colourless prisms of M. P. 220-222 C. and of specificrotation [a] =+148:4(c=0.434 in acetone) What is claimed is:

1. A process for the preparation of a 17,20-hydroxy-ketone of thepregnane series, which comprises reacting a pregnene having the grouping=CHC'H2X in the ll-position, X representing a member selected from thegroup consisting of free, esterified and etherified hydroxyl, withosmium tetroxide and with a member selected from the group consisting ofhydrogen peroxide, an alkyl peroxide and a peracid, the reactants beingexposed to light during the reaction, and isolating the resultant17,20-hydroxy-ketone from the reaction mixture.

2. A process for the preparation of a 17,20- hydroxy-ketone of thepregnane series, which comprises reacting a A -3-keto-pregnene havingthe grouping =CHCH2X in the 17-position, X representing a memberselected from the group consisting of free, esterified and etherifiedhydroxyl, with osmium tetroxide and with a member selected from thegroup consisting of hydrogen peroxide, an alkyl peroxide and a peracid,the reactants being exposed to light during the reaction, and isolatingthe resultant 17,20-hydroxy-ketone from the reaction mixture.

3. A process for the preparation of a 17,20-hydroxy-ketone of thepregnane series, which comprises reacting a 3-acyloxy-pregnene havingthe grouping =CH-CH2X in the 17-position, X representing a memberselected from the group consisting of free, esterified and etherifiedhydroxyl, with osimium tetroxide and with a member selected from thegroup consisting of hydrogen peroxide, an alkyl peroxide and a peracid,the reactants being exposed to light during the reaction, and isolatingthe resultant 17,20-hydroxy-ketone from the reaction mixture.

4. A process for the preparation of a 17,20-hydroxy-ketone of thepregnane series, which comprises reacting a 3,11-diketo-pregnene havingthe grouping =CHCH2X in the 17 -position, X representing a memberselected from the group consisting of free, esterified and etherifiedhydroxyl, with osmium tetroxide and with a member selected from thegroup consisting of hydrogen peroxide, an alkyl peroxide and a peracid,the reactants being exposed to light during the reaction, and isolatingthe resultant 17,20-hydroxy-ketone from the reaction mixture.

5. A process for the preparation of a 17,20-hydroxy-ketone of thepregnane series, which comprises reacting a A"-3-keto-2l-acetoxy-pregnadiene with osmium tetroxide and with a memberselected from the group consisting of hydrogen peroxide, an alkylperoxide and a peracid, the reactants being exposed to light during thereaction, and isolating the resultant 17,20-hydroxy-ketone from thereaction mixture.

KARL MIESCI-IER. JULIUS SCHMIDLIN.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,225,756 Pincussen Dec. 24, 1940 2,275,790 Miescher Mar. 10,1942 2,341,288 Pruckner Feb. 8, 1944 2,437,564 Serino Mar. 9, 19482,492,194 Sarett Dec. 27, 1949 2,543,817 Weil Mar. 6, 1951

1. A PROCESS FOR THE PREPARATION OF A 17,20-HYDROXY-KETONE OF THEPREGNANE SERIES, WHICH COMPRISES REACTING A PREGNENE HAVING THE GROUPING=CH-CH2X IN THE 17-POSITION, X REPRESENTING A MEMBER SELECTED FROM THEGROUP CONSISTING OF FREE, ESTERIFIED AND ETHERIFIED HYDROXYL, WITHOSMIUM TETROXIDE AND WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OFHYDROGEN PEROXIDE, AN ALKYL PEROXIDE AND A PERACID, THE REACTANTS BEINGEXPOSED TO LIGHT DURING THE REACTION, AND ISOLATING THE RESULTANT17,20-HYDROXY-KETONE FROM THE REACTION MIXTURE.